Quaternary ammonium salts of lower alkyl 4-substituted-2-(tertiaryaminoalkoxy) benzoates and their preparation



Patented June 16, 1953 QUATERNARY AMWONIUM SALTS F LOW- ER ALKYL 4-SUBSTITUTED-2- (TERTIARY- AMINOALKOXY)BENZOATES AND THEIR PREPARATION Raymond 0. Clinton, North Greenbush, and

Stanley 0, Laskowski, Menands, N. Y., assignors to Sterling Drug Inc., New York, N. Y., a

corporation of Delaware No Drawing. Application September 5, 1951, Serial No. 245,248

Claims. "1 This invention relates to quaternary ammonium salts of lower alkyl 4 substituted 2- (tertiary aminoalkoxy)benzoates and to their preparation.

The quaternary ammonium salts of our in 'vention have the general formula where Z is nitro, amino, lower alkylamino or .lower hydroxyalkylamino, X is a lower alkylene radical, NRRi is a tertiary-amino radical, Re is a lower alkyl radical, R4 is a lower alkyl radical or a benzyl radical and An is a nontoxic anion. These compounds of our invention have useful pharmacological properties, such as ganglionic blocking activity.

In the above general formula, the lower alkylene radical designated as X has preferably two to four carbon atoms and has its two free .valence bonds on different carbon atoms. Thus, X includes such examples as and the like. The tertiary-amino radical shown above as NRR1 comprehends dialkylamino radicals where R and R1 are lower alkyl groups, alike or different, and each alkyl group having one to six carbon atoms, such dialkylamino radicals including dimethylamino, diethylamino, ethylmethylamino, diisopropyl amino, ethyl n propylamino, di n butylamino, di-n-hexylamino, and the like. Further, the tertiary-amino radical designated as NRR1 encompasses saturated N-heteromonocylic radicals having five to six ring atoms, illustrated by examples such as l-piperidyl; (lower alkylated) l-piperidyl such as Z-methyl-l-piperidyl, 3- ethyl-l-piperidy'zl, 4 :methyl ,-.1 piperi'dyl, 2,6.-

'salts as a whole are effective.

dimethyl l piperidyl; 1 pyrrolidyl; (lower alkylated) 1 pyrrolidyl such as 2-methyl-1- pyrrolidyl, 2,5 dimethyl 1 pyrrolidyl; 4- morpholinyl; and the like. In the above formula, when Z stands-for -lower' alkylamino, the lower alkyl radical, designated as R3 hereinbelow, has preferably one to six carbon atoms, including such radicals as methyl, ethyl, n-propyl, nbutyl, isobutyl, n-amyl, 2-amyl, n-hexyl, and the like. When Z represents lower hydroxyalkylamino, the lower hydroxyalkyl' radical, designated as R3 hereinbelow, has preferably two to six carbon atoms, including radicals such as 2-hydroxyethyl, 2-hydroxypropyl, 3- hydroxypropyl, 3-hydroxy-2-methylpropyl, '3- hydroxy 2,2 -dim'ethylpropyl,.2 hydroxy butyl, 4 hydroxybutyl, 3 'hydroxyam'yljfihydroxyamyl, fi-hydroxyhexyL- andthe like.

R4 when representing lower alkyl has preferably one to six carbon atoms, including such radicals as methyl, ethyl, n-propyl, n-buty-l, isobutyl, n-amyl, n-hexyl, and the like. The

'non-toxic anion, designated above as An, which can be any anion, for instance chloride, bromide, iodide, sulfate, benzenesulfonate, para-toluenesulfonate, and the like, has no appreciable pharmacological activity of its own in thehigh dilutions at which the quaternary ammonium In particular, the anions contribute nothing to the ganglionic blocking activity which resides solely in th remainder of the molecule.

Thus, our invention comprehends quaternary ammonium salts of the above defined lower alkyl 4 substituted 2 (tertiary aminoalkoxy)benzoates, said salts being derived from lower alkyl or benzyl esters of an acid, either inorganic or organic, such esters having the chlorides, metho-para-toluenesulfonates, ethopara-toluenesulfonates, ethobenzenesulfonates, and the like.

The parent lower, alkyl 4 substituted 2 (tertiary-aminoalkoxy)benzoates are disclosed and claimed in our copending application Serial Number 245,244, filed September 5, 1951, and they can be prepared preferably according to the procedure represented by the following series of equations where X, NRR1,R2 and Rs have the meanings given hereinabove and halogen is chlorine, bromine, iodine or fluorine:

I halogen-X-NRR, OH OX-NRR C O R: C O 0 R2 NHRa NHz III OXNRR I 0XNRR1 O 0 R2 0 0 R2 Thus, in step I, a lower alkyl 4-nitro-2-hydroxybenzoate (A) is converted into a lower alkyl 4 nitro 2 (tertiary aminoalkoxy)benzoate (C) by reaction with tertiary-aminoalkyl halide (B). In step II, the lower alkyl l-nitro-2- (tertiary-aminoalkoxy)benzoate (C) is reduced to yield the corresponding lower alkyl l-amino- 2-(tertiary-aminoalkoxy)benzoate (D), which is then alkylated to form the corresponding lower alkyl l-alkylaminoor 4-hydroXyalkylamino-2- (tertiary-raminoalkoxy) benzoate (E) illustration of this series of reaction is the formation of ethyl 4-n-butylamino-2-(2-diethylaminoethoxy)benzoate by first reacting ethyl .4 nitro 2 hydroxybenzoate, preferably in the form of an alkali metal salt, with a 2-diethylaminoethyl halide, preferably the chloride,

to yield ethyl 4- nitro 2 (2 diethylaminoethoxy) benzoate, reducing this 4-nitro compound to yield the corresponding ethyl 4- amino 2 (2 diethylaminoethoxy)benzoate and then alkylating this 4-amino compound to produce ethyl 4 n butylamino 2 (2 diethylaminoethoxy) benzoate.

Step I is carried out preferably using a lower alkyl 4-nitro-2-hydroxybenzoate in the form of a metal salt, with a tertiary-aminoalkyl halide. Alternatively, step I can be carried out using a lower alkyl 4-nitro-2-hydroxybenzoate itself, however, with a resultingdecrease in yield of the lower alkyl 4-nitro-2-(tertiary-aminoalk-,

oxy) benzoate.

The reduction step II is carried out either by chemical methods or by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. In practicing our invention, we preferably used iron and hydrochloric acid. Catalysts suitable when catalytic hydrogenation is catalyze hydrogenation of nitro groups to amino groups.

The alkylation of the lower alkyl 4-amino-2- (tertiary-aminoalkoxy)benzoates (D) to produce the related lower alkyl 4-alkylaminoor i-hydroxyalkylamino-benzoates (step III) where R3 has from three to six carbon atoms is eferably carried out by reductively alkylating the 4-amino compound with an alkanal or a hydroxyalkanal.

Thus, this preferred method of alkylating the 4951111110 benzoates (D) is by treating a mixture of a-lower alkyl 4-amino-2-(tertiary-aminoalkoxy)benzoate and an alkanal or hydroxyalkanal, having from three to six carbon atoms, in a reducing medium. This reduction is carried out either by chemical methods or by catalytic hydrogenation. Illustrative of this reductive alkylation step is the formation of n-propyl 4-hamylamino 2- [2 (l-piperidyl)ethoxylbenzoate employed include Raney nickel, platinum, palor n-propyl 4- (S-hydroxyamylamino) -2- [2- lpiperidyl) ethoxylbenzoate by treating a mixture of the corresponding n-propyl 4-amino-2-[2-(L- ;.piperidyl)ethoxylbenzoate with pentanal (Valeraldehyde) or fl-hydroxypentanal, respectively, with chemical reducing agents, such as zinc dust and acetic acid, iron and acetic acid, iron and hydrochloric acid, etc., or with hydrogen under pressure using catalysts such as platinum, palladium, Raney nickel or other catalysts generally effective in reductive alkylations using alkanals and hydroxyalkanals.

Alternatively, the alkylation step III can be carried out directly by heating a lower alkyl 4- amino-Z- (tertiary-aminoalkoxy) benzoate (D) with an alkylating agent such as methyl iodide, ethyl bromide, n-propyl bromide, isobutyl iodide, Z-hydroxyethyl bromide, 4-hydroxybutyl chloride, and the like, in the presence of a hydrogen halide acceptor, e. g., sodium bicarbonate, potassium carbonate, etc. Thus, such treatment of ethyl 4-amino-2- (3-diethylaminopropoxy) benzoate with methyl iodide, ethyl bromide or 2-hydroxyethyl bromide yields, respectively, ethyl 4- methylamino 2- (3 diethylaminopropoxy)benzoate, ethyl 4-ethylamino-2-(B-diethylarhinopropoxy)behzoate or ethyl 4-(2-hydroxyethylamino) 2- 3 diethylaminopropoxy) benzoate. Yields of the resulting lower alkyl -alkylaminoand Q-hydroxyalkylamino-Z-(tertiary-aminoalkoxy)benzoates obtained by this method are lower than those obtained by the foregoing described reductive alkylation procedure due to quaternary formation in this reaction.

Step I can also be carried out stepwise, that 16,.

by first haloalkylating a lower alkyl 4r-I1itI'O-2- hydroxybenzoate (A) to form a lower alkyl 4- nitro-Z-(haloalkoxy) benzoate which is then treated with a secondary amine having the formula I-INRR1. The first step can be accomplished by treating either a lower alkyl 4-nitro- 2-hydroxybenzoate or a metal salt thereof with a haloalkylating agent such as a haloalkyl paratoluenesulfonate, haloalkyl benzenesulfonate, dihaloalkane, etc. procedure, ethyl 4-nitro-2-hydroxybenzoate is haloalkylated by treating its sodium salt with 2-chloro-ethy1 para-toluenesulfonate to form ethyl 4-nitro-2-(2 chloroethoxy) benzoate which then is treated with diethylamine or piperidine to form ethyl 4-nitro-2-(2--diethylaminoethoxy) benzoate or ethyl 4-nitro-2-[2-(l-piperidyl)- ethoxylbenzoate, respectively.

The quaternary ammonium salts of our present invention are prepared according to the process' as illustrated for the methiodides by thefol- As illustrations of this stepwise lowing series of equations where X, NRRi, R2 and R3 are defined as above:

In step IV, a lower alkyl l nitrQ-Z-(tertiary- 'aminoalkoxy)benzoate (C) is treated with methyl iodide to yield the correspondingv lower alkyl 4-nitro-2- (tertiary-aminoalkoxy) b enzoate methiodide (F) I'n-step 'V, the l-nit'rio methiodide (F) is reduced to yield'the corresponding lower alkyl 4--amino-z-(tertiary-aminoalkoxy) benzoate methiodide (G), which, in step VI, is alkylated 'to produce the corresponding lower alkyl 4-alkylaminoor 4-hydroxya1kylamino-2-(tertiary aminoalkoxy benzoate methiodide (H). As a.

"specific illustration of this series of reactions,

ethyl 4-nitro-2- (2-diethylaminoethoxy) benzoate is treated with methyl iodide to form ethyl 4 nitro-Z- (Z-diethylaminoethoxy) benzoate methiodide, which is then reduced to yield the corresponding ethyl 4-amino-2-(Z-diethylaminoeth- -oxy)benzoate methiodide, which, in turn, is alkylated to yield ethyl 4-n-bu'tylamino-2-:(2-di- 'ethylaminoethoxy)benzoate methiodide.- I

When, in step IV, other lower alkyl or ,benzyl esters of an acid is substitutedfor methyliodide,

the corresponding 4-nitro (F), 4-amino (G and A5 4-substitumd-amino (H) quaternary salts are formed. Other lower alkyl and benzyl esters that are suitable include those shown hereinabove.

The reduction step V is carried out preferably by catalytic hydrogenation using such catalysts as Raney nickel, platinum, palladium or other oatalysts generally effective to catalyze nitro groups to amino groups. Alternatively, butless desirably, this reduction step can" be carried out by chemical methods. Suitable chemical reducing agents include ironand a hydrohalic acid, tin an a hydrchalic acid, etc.-- i

The alkylation step VI to produce the lower alkyl l-alkylaminoor 4-hydroxyalkylamino-2- (tertiary-aminoalkoxy) benzoate quaternary salts v where the alkyl or .hydroxyalkyl radical, desig- .'nated as R3,'has from three to six carbonatoms. V

is preferably carried out by reductively'alkylating the corresponding 4-amino'quaternary salts with an alkanal or a hydroxyalkanal'havingirom three to six carbon atoms. This reduction is carried out preferably by catalytic hydrogenation using catalysts such as platinum, palladium, Ptaney nickel or other catalysts generally effective in reduction alkylation using alkanals and hydroxyalkanals. Alternatively, this reductive alkylation procedure can be carried out, but :with lower yields, by chemical-methods using chemical reducing agents such as 'zinc and acetic acid, etc.

Alternatively, but less desirably, the alkylation step VI can be done directlyby heating alo. er alkyl 4-amino-2-(tertiary-aminoalkoxy).benzoate quaternary salt with an alkylating agentsuch-as methyl iodide, ethyl bromide, n-propyl-bromide, isobutyl iodide, 2-hydroxyethyl bromide,v Ae-hydroxybutyl chloride, and the like, .in the presence .of axhydrogen'halide. acceptor, e ge sodium bicarbonate, potassium carbonate; Thus, such treatment of ethyl 4-amino-2- (3 -diethylaminoe propoxy.) benzoate methiodide with methyl iodide, ethyl bromide or Z-hydroxyethyl bromide yields, respectively, ethyl 4-methylamino-2- (3-diethylaminopropoxylbenzoate methiodide, ethyl 441th.- ylamino 2 (3 diethylaminopropoxy)benzoate methiodide or ethyl 4-(2-hydroxyethylamino) -2- (3 diethylaminopropoxy)benzoate methiodide. Yields of the resulting lower'alkyl 4-alkylaminoand 4-hydroxyalkylamino-2-(tertiary-aminoalv hoxylbenzoate quaternary salts obtainedby. this rneth od are lowerthan those obtained by the-fore,- going; describedreductive alkylation procedure due to, oyeralkylation and anion exchange redo:-

I Q 7 -J" The lower alkyl el-alkylaminoand 4-hydroxy; .alkylamino- .2 (tertiary-aminoalkoxyl benzoate quaternary salts can also be. prepared, hilt- 11655 preferably-,by, treating :a lower alkyl i -alkylwith an alkyl or benzyl ester of an inorganicbr organic acid, said esters beingof thetype described above. Thus, treatment of ethyl 4,-n-amylaminoor 4 ('5-hydroxyamylamino) -2- 2 2,6,-di methyl-l-piperidyl) ethoxy] benzoate with methyl iodide results in the formation of ethyl 4-n-am'yl}- amino 2 [2 (2,6 dimethyll piperidyl) ethoxyl benzoate methiodide or ethyl '4-(5-hy droxyainylamino) 2 [2 (2,6 dimethyl 1 piperidybethoxylbenzoate methiodide. Using benzyl chloride in place of methyl iodide yields ethyl 4-n-amyla-mino-2- [2- ('Zfi-dimethyI-I-piperidyDethoxylbenzoate benzochloride or ethyl 4. (5 hydroxyamylamino) 2 [2-(2,6,- dimethyl-l-piperidyl)ethoxylbenzoate. benzochloride, respectively.

'amino'alkoxwbenzoate quaternary salts'can be prepared, but less preferably, by treating, pref- ..erably at room temperature, the corresponding lower alkyl 14-amino-2-(tertiary-aminoalkoxy) benzoates designated above as .(D), withan alkyl or benzyl ester of an inorganic or organic acid of the type described hereinabove. Thus, treatment of methyl 4-amino-2- [3- l-pyrrolidyl) propoxyl benzoate with methyl iodide or benzyl chloride results'in the formation of methyl 4-am'ino-2- [3- (l-pyrrolidyl) propoxy] benzoate methiodide or methyl 4-amino-2- [3- (1Dy rolidyl) propoxy] benzoate benzochloride, respectively. This 'mode' of preparation is not, as desirable as the foregoing.

Preparation of. the lower alkyl 4-nitro-2-(t er- 7 tiaryeaminoalkoxy) benzoates. is illustrated bythe Similarly, the lower alkyl 4-amin0-2-(tertiarycake was washed with hot toluene.

C. (cor.).

following alternative procedures, all of which involve alkylation of a'lower alkyl 4-nitro-2-hydroxybenzoate or a metal salt thereof with a tertiary-aminoalkyl halide, or, stepwise, with a haloalkylating agent such as a haloalkyl paratoluenesulfonate to produce a lower alkyl 4-nitro- -2-(haloalkoxy)benzoate which is then treated with a secondary amine to form the desired lower" alkyl 4-nitro-2- (tertiary-aminoalkoxy) benzoate.

Ethyl 4-nitro-2- (2-diethylaminoethoxy) benzoate was prepared as follows: To a stirredrefluxing solution of 42.2 g. of ethyl 4-nitro-2- hydroxybenzoate in 1000 ml. of absolute alcohol was added slowly a solution of 4.6 g. of sodium in 500 ml. of absolute ethanol. To the resulting deep red solution was added, with stirring over a period of about twenty minutes, 27.1 g. of Z-diethylamin'oethyl chloride and the resulting mixture was refluxed for about three hours. An additional g. of Z-diethylaminoethyl"chloride was then added and refluxing continued for an additional thirty minutes. The reaction mixture was cooled in ice, filtered, and the filtrate taken to dryness in vacuo. The residue was taken up in 500 ml. of ethyl acetate,the're- V 'sulting solution filtered and the filtrate taken to dryness, yielding ethyl 4-nitro-2-'-(2-diethyl- 'aminoethoxy)benzoate.' This compound was converted into its hydrochloride addition salt by dissolving it in a small amount of ethyl acetate and treating the solution with an excess "of 20% ethereal hydrogen chloride solution. The resulting precipitate of ethyl 4-nitro- 2-(2-di- 'ethylaminoethoxy)benzoatc hydrochloride was collected and recrystallized twice from isopro- 'panol, yielding 45.5 g. of purified product,'M. P.

144.4-145.2 C. (cor.). r x AnaZ.Calcd. for CHz2N2OaHCl: C, 51.94;

H, 6.40; 01, 10.22. Found: 0, 52.08; H, 6.48; (31,

Ethyl 4-nitro-2- (Z-diethylaminoethoxy) benzoate was also prepared stepwise as follows: A mixture of 84.4 g. of ethyl 4-nitro-2-hydroxy- 'benzoate, 60.8g. of powdered anhydrous potassium carbonate and 2000 ml. of meta-xylene 'was' refluxed with stirring under a water trap until no more water was collected (three hours). :The Water trap was removed and 112.7 g. of 2- chloroethyl para-toluenesulfonate was added in one portion. Refluxing and stirring were continued for an additional nineteen hours. The mixture was filtered while hot and the filter- The combined filtrate and washings were evaporated to Several recrystallizations of this .benzoate as pale yellow platelets, M. P. 56.6-57.2

AnaZ.-Calcd. for C11H12C1N0si C1, 12.96.

.Found: Cl, 12.62.

.On heating a mixture of ethyl 4-nitro-2-(2- .chloroethoxy) benzoate, diethylamine, sodium .iodide and absolute ethanol, there was obtained,

"in only a fair yield, ethyl 4-nitro-2-(2-diethyl .aminoethoxy) benzoate.

Following this same procedure but using dimethylamine or 2-methyl- .piperidine in place of diethylamine, there is ob- 'sodiumchloride was filtered ofi and washed with ethyl acetate. The combined filtrate and washings were taken down to dryness under reduced pressure yielding a. mixture of an oily residue and a small amount of a red solid. To this mixture was added 2 liters of ether and the insoluble red solid was filtered off. The filtrate was evaporated to dryness under reduced pres-' sure, yielding, as an oily material, ethyl 4-nitr0- 2- [3- l-piperidyl) propoxy] benzoate. This ester was converted into its hydrochloride salt by dissolving it in a little ethyl acetate and adding to the solution anexcess of ethanolic hydrogen chloride. The solid hydrochloride separated slowly. The mixturewas diluted with absolute ether, cooled, and the'precipitate was collected and washed with absolute ether. The precipitate was recrystallizedthree times from isopro- 'panol, yielding, as pale yellow needles, ethyl 4:- nitro --2 [3 (l-piperidyl)propoxylbenzoate hydrochloride/M. P. 160.4161.6 C. (cor.).

Anal.-Calcd. for C17H24N2O5.HC1: N 7.52; CI, 9.51. Found: N 7.37; Cl, 9.33.

N stands for total nitrogen as determined by the Dumas method.

n-Butyl 4-nitro-2- (Z-diethylaminoethdxy) benzoate was prepared as follows: To a stirred refluxing solution of 9.2 g. of sodium in 2000 ml. of n-butanol was added 95.7 g. of n-butyl 4- nitro-Z-hydroxybenzoate. The red insoluble sodium phenolate separated immediately. After addition had been complete, refluxing was continued for an additional ten minutes, and then 542g. of 2-diethylaminoethyl chloride was added dropwi'se over a period of abouttwentyminutes. When the addition had been completed, the color had already changed from a deep red to a pale orange-yellow. The reaction mixture was then refluxed for five hours, cooled and filtered. The

filtrate was taken downto dryness under 're-.

duced pressure yielding an oily residue and a small amount of red solid. This mixture was treated with 2500 ml. of absolute ether, and the red solid was filteredofi. The filtrate was taken down to dryness under reduced pressure, yielding, as an oil, the product, n-butyl 4-nitro-2-(2- diethylaminoethoxy)benzoate. This ester -was converted into its hydrochloride addition salt by dissolving. it in a little absolute ether and. treating the solution with an excess of ethereal hydrogen chloride. A pale cream-coloured solid separated. The mixture was cooled and the solid was collected and washed with absolute ether.

Three recrystallizations. of this solid from: ethyl acetate yielded, as pale yellow needles, n-butyl 4 .nitro-2- (2-diethylaminoethoxy) benzoate hy drochloride, M. P. 1176-11813 C. (cor.).

' AnaL-Calcd. for C17I-I2eN2O5.I-IC1Z N 7.47; Cl, 9.46. Found: N 7.66; Cl, 9.44.

Ethyl 4-nitro-2- (2-dimethylaminoethoxy) ben zoate was prepared as follows: To a'solution of 126.6 g. of ethyl4-nitro-2-hydroxyhenzoatein 1000 ml. of absolute ethanol was added a solution of 13.8 g. of sodium in 500 ml. of absolute ethanol. The ethanol'was' then removed by distillation While simultaneously adding toluene To the resulting bright red suspension of the sodium salt of ethyl 4-nitro-2-hyuct was ethyl 4-nitro-2-(2-dimethylaminoeth-- oxy)benzoate hydrochloride; Anal.-Calcd. for C13H18N205HC1Z 01,1112. Found: ND, 8.56; Cl. 11.10. 7

Additional lower alkyl 4-nitro-2-(tertiaryaminoalkoxy benzoates, in the form of their hydrochlorides, prepared according to the above described procedures are given in Table 1 TABLE I I ITTO:

aminoalkoxy) benzoates, as described hereinabove. Illustrative of this reduction'are the following examples.

Ethyl 4-amino-2-(2 diethylaminoethoxy) benzoate was prepared as follows: To a hot vigorously stirred mixture of 33.6 g. of powdered iron, 1 ml. of concentrated hydrochloric acid'and 200 ml. of aqueous ethanol was added slowly, over a period of about ten minutes, 35.7 g. of ethyl l-nitro 2-(2 diethylaminoethoxy)benzoate hydrochloride. The resulting mixture was heated withstirring for another thirty minutes, after which an excess of solid sodium bicarbonate (about 15 g.) Was added. The mixture was stirred for an additional ten minutes and then filtered through a filter aid which was subsequently washed with hot ethanol. filtrate and washings were concentrated by distilling in vacuo, thereby yielding an oily residue which was taken up with ethyl acetate. The ethyl acetate was dried over anhydrous calcium The combined C O 0 R2 Analyses U n NRR; B: ay Formula ND- 01 Galcd. som Calcd. Found 2 NC- HH CHzCHa 153. 0-154. 0 CmHztNnOaHcl 7. 24 7. 15 9. 16 I 9. 14 2 N C4EO OHZCHB 20?. 0-208. 0 CIISHZONIOfl-HCH 7. 77 7. 81 9. 83 9. 92 3 NC4HsO CHaCHa 142. 0-144. 6 C16H22N20o.HC1 7. 48 7. 79 9. 46 9. 25 2 NC H 0H2CH3 191. 0-191. 5 CmHzzNzOsHCl 7. 81 7. 88 9. 88 9. 90 2 N C4H$O CH; 206. 0-206. 4 OHHNNZOLHCl e 4. 04 e 4. 05 10. 22 10. 21 2 N OeH 015120113 180. 8-182. 6 CnHzlNvOaHCl 7. 52 7. 22 9. 51 9. 38 3 NCaHn OHZCH3 158. 2-159. 6 ClfiHZfiNlOs-HGI 7. 24 7. O3 9. 16 8. 92 3 N(CH5)2 01120113 16 1. 8-165. 6 mHuNzOsJHJl 7. 77 7.87 9. 83 9. 72 2 N(C-2H5)2 CHzCHzCHa 153. 4-155. 4 OlfiHZANflOE-HOI 7. 77 7. 83 9. 83 9. 83 2 N(CzH )z CH 156. 9-159. 2 O14H2oNzOs.HC1 8. 42 8. 38 10. 65 10. 5O

hexyl (2) Lower alkyl 4-amino-2 (tertiary aminoab koxy) benzoates These compounds are prepared by reduction of the corresponding lower alkyl 4-nitro-2- (tertiarydetermined by titration with standard titanous chloride in glacial acetic acid solution.

sulfate and. taken to dryness in vacuo yielding, as a pale orange, slightly viscous oil, 27.4 g. of the product, ethyl 4-amino-2-(2-diethylaminoethoxy)benzoate.

Alternatively, the foregoing preparation canbe carried out using ethyl 4-nitro-2-(2-diethylaminoethoxy)benzoate in place of ethyl 4-nitro- 2 (2 diethylaminoethoxy)benzoate hydrochloride.

The preparation of ethyl 4-amino-2-(2-diethylaminoethoxy) benzoate is in the form of its monohydrochloride salt was accomplished as follows: To a solution of 12.0 g. of ethyl 4amino-2(2 diethylaminoethoxy)benzoate dissolved in 50 ml. of absolute ethanol was added,8.50 ml. of an ethanolic solution of hydrogen chloride (0.1843 g./ml.; enough HCl to produce the monohydrochloride). The solution was mixed well, taken to dryness in vacuo, ethyl acetate added and removedin vacuo, and the remaining residue dissolved in a small amount of isopropanol. To this solution was added a small amount of ethyl acetate and ether, just enough-to produce turbidity, whereupon spontaneous crystallization resulted. The mixture was then diluted with ether, cooled in ice and the precipitate collected. Two recrystallizations from this precipitate from acetone-ethyl acetate yielded, as rosettes of white prisms, ethyl 4-amino-2- (2-diethylaminoethoxy) benzoate monohydrochloride, M. P. 134-135 C.

AnaZ.Calcd. for C15H24N2O3.HC11 Cl, 11.19. Found: Cl, 11.20.

The dihydrochloride salt of the above 4-amino benzoate was prepared by dissolving it in ethyl acetate and treating the solution with an excess of ethereal hydrogen chloride. The mobile colorless oil which separated crystallized readily when triturated. The solid was filtered, washed well with ethyl acetate and recrystallized twice from absolute ethanol-ethyl acetate. There was thus obtained ethyl 4 amino 2 (2 diethylamino ethoxy benzoate dihydrochloride, M. P. 173.63- 173.9 C. (con) [dried three days at 50 C.].

AnaZ.-Calcd. for C15H24N2O32HC1: C, 50.99; H, 7.42; Cl, 20.07. Found: C, 51.14; H, 7.36; Cl, 19.90.

Ethyl 4 amino 2 (2 diethylaminoethoxy) benzoate was converted into its phosphoric aicd addition salts as follows: A solution of the ester in absolute ethanol was treated with a molar equivalent of 85% phosphoric acid in absolute ethanolic solution. The precipitated crystalline phosphate was collected and recrystallized four times from 95% ethanol, yielding ethyl 4-amino- 2 (2 diethylaminoethoxy) benzoate phosphate, M.P. 168.7-1696" C. (coin).

AnaZ.-Calcd.. for C15H27N205P2 H3PO4, 25.91; ND, 7.40. Found: H3PO4, 25.30; ND, 7.41.

n-Butyl 4-amino-2- (2-diethylaminoethoxy) benzoate was prepared as follows: A stirred mixture of 71.5 g. of powdered iron, 300 ml. of ethanol,

all

75 ml. of water and 1 ml. of concentrated hydrochloric acid was brought to a boil. Heat was removed and 80.0 g. of n-butyl 4-nitro-2-(2-di ethylaminoethoxy)benzoate hydrochloride was added portion-wise at such a rate as to maintain gentle boiling. After addition of the nitro compound had been completed, the reaction mixture was refluxed with stirring for thirty minutes. Then an excess of sodium bicarbonate (about 20 g.) was cautiously added and refluxing and stirring were continued for an additional ten minutes. The reaction mixture was filtered hot and the filtrate was concentrated in vacuo to remove all the ethanol. The product, which separated as distinct layer, was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous calcium sulfate and concentrated in vacuo to yield, as a straw colored oil, n-butyl 4 amino 2 (2 diethylaminoethoxy) benzoate. This ester was converted into its phosphoric acid addition salt as follows: To a hot solution of 46 g. of n-butyl- 4-amino-2-(2-diethylaminoethoxy) benzoate dissolved in a minimum quantity of hot absolute ethanol was added a hot ethanolic solution of 17.2 g. of 85% phosphoric acid. A white solid readily separated from the hot solution, which was diluted with ethyl acetate, cooled and filtered. The solid was recrystallized several times from absolute ethanol containing a small quantity of water, thereby yielding. as rosettes of white needles n-butyl 4-amino-2-(2-diethylaminoethoxy)benzoate phosphate, M.P. 154.5 l55.5 C. (con).

Anal.-Calc'd. for C17H28N203-H3PO4I ND," 6.88; H3PO'4, 24.12. Found: ND, 7.10; H3PO 4, 24.15.

Ethyl 4-amino 2 [3 (1-piperidyl) propoxylbenzoate was prepared according to the procedure described above for the preparation of ,n-butyl 4-amino-2- (Z-diethylaminoethoxy) benzoate but using 67.2 g. of powdered iron, 400 ml. of ethanol,- 100 ml. of water, 1 ml. of concentratedhydrochloric acid, 76 g. of ethyl 4 nitro 2 [3- (1.- piperidyl)propoxylbenzoate hydrochloride and about 60 g. of sodium bicarbonate. Vacuum evaporation of the ethyl acetate extract yielded a solid product. This solid when recrystallized from ethanol yielded, as white needles, ethyl 4-amino- 2- [3- (l-piperidyl) propoxy] benzoate, M.P. 109.2- 110.1 C. (con).

AnaZ.--Calcd. for Owl-126N203: ND, 9.14. Found: ND, 8.90. I

Ethyl 4 amino 2- [3-(1-piperidyl) propoxylbenzoate phosphate, prepared as above, melted at 160.2-161.6 C. (cor.) when recrystallized several times from absolute ethanol.

Anal.Calcd. for C17H26N203.H3PO43 ND, 6.93; H3PO4, 24.22. Found: ND, 6.83; H3PO4, 24.37.

Methyl 4-amino-2- [2-(4-morpholinyl) ethoxyl benzoate was prepared according to the foregoing procedures but using 13.15 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 400

ml. of 75% aqueous methanol and 13.6 g. of methyl 4-nitro-2 [2- 4-morpholinyl) ethoxy] benzoate hydrochloride. The product, methyl 4 amino 2 [2 (4 morpholiny1)ethoxy] benzoate, was obtained as an oil. This ester was converted into its diphosphate as follows: A solution of 9.5 g. of methyl 4-amino-2-[2-(4-morpholinyDethoxylbenzoate in 25 ml. of methanol was treated with a solution of 3.19 g. of phosphoric acid in 25 ml. of methanoL'whereupon there separated immediately a gummy material. Ethyl acetate was added to the mixture and the precipitated material was triturated while warming. The supernatant liquid was decanted and the gummy material was triturated several times with warm absolute ethanol, whereupon solidification finally resulted. The solid was filtered and recrystallized 'by suspending it in hot absolute ethanol and adding hot water dropwise until the solution became clear, treating the solution with decolorizing charcoal, filtering and allowing the filtrate to cool. The finely divided white salt that separated was collected and dried in vacuo at C., yielding 5.5 g. of methyl 4-amino-2-[2-(4- morpholinyl)ethoxylbenzoate diphosphate, M.P. 151.3-152.1 C. (con).

Anal.-Calcd. for C14H20N2042H3PO42 ND, 5.88 2H3PO4, 41.16. Found: ND, 5.96; 2H3PO'4, 40.85.

The foregoing reductions of the lower alkyl 4 nitro 2 (tertiary-aminoalkoxy) benzoates to 'yield the corresponding 4-amino benzoates can be carried outby catalytic hydrogenation as illustrated by the following general preparation: Ten grams of the lower alkyl 4-nitro-2-(tertiaryaminoalkoxy benzoate in ml. of ethanol is hydrogenated using 50 lbs. pressure of hydrogen at 25 C. in the presence of 2 g. of Raney nickel. After the rapid exothermic reaction, the catalyst is filtered ofi and the filtrate evaporated to drynessQ The resulting residue is dissolved in absolute ethanol and is treated with a solution of 85% phosphoric acid in absolute ethanol to yield the corresponding lower alkyl 4-amino-2-(tertiary-aminoalkoxy) benzoate phosphate.

Additional lower alkyl 4-amino-2- (tertiaryaminoalkoxy)benzoates, in the form of their monophosphate' salts, prepared according to the above procedures are given in Table II.

- '14 times with benzene. After the combined benzene layer and extracts had been dried over anhydrous TABLE H O(CH:),NRR1 H:PO4

Analyses 7. NRR1 a. Formula H.1 0; ND

(con) Calcd. Found Galcd. Found 2 N(C2Hs)1 Ilse/3H7 l53.0154. 0 CzoHroNaOrP 24. 98 25. 23 7. 14 7. 1 5 3 N(CzH )z C2115 151. 5-153. 2 QmHzqNaOiP 24. 98 25. 00 7. 14 7. O5 2 NCaHic C2H5 20. 8-221. 4 CmHnNzOfi 25. 11 25. 41 7. 18 7. 17 2 NCaH1z- C2115 2 NC7H 02H; 211. 0-211. 8 C18H31N201P 23. 43 23. 60 6. 70 6 67 3 Nos Hu (31H; 136. 4-138. 3 C13H3 N2O1P 23. 43 23. 12 6. 7O 6. 56 2 NClHsOB- CzHa 196. 3-196. 9 OJBHZBNlOEP 24. 99 24. 50 7. 14 7. l6 3 NCsB'aOb 03115 143. 3-144. 4 oioHnNiosP 24. 12 24. 00 6.89 6. 65 2 N(CH3)2 02B} 176. 3-177. 3 OnHnNnO-r? 27. 98 28. 10 8. O0 7. 98

NI)IL 9.40.

NCaH z=2-methyl-1-piperldyl. d The crystalline base melted at 91.292.4 0. (con). N]; 9.26;

- N C-[H1 =2,6 diInetl1yl-l-piperidyl.

Ulhe crystalline base melted at ll2.4-1l3.5 0. (con).

'z NO4HB0=4-morphollnyL I b The crystalline base melted at 98.0-99.8 0. (con).

i The crystalline base melted at 106.8l08.0 0. (con).

(3) Lower alkyl 4-:allcylaminoand 4-hydromyaZlcyZamino-Z- (tertiary-aminoalkowy) benaoates These compounds are produced by alkylation of the corresponding lower alkyl 4-amino-2- (tertiary aminoalkoxy benzoates described above. This alkylation is run preferably by reductive alkylation procedures as illustrated in the following examples.

- Ethyl 4 n butylamino 2 (2 diethylaminoethoxy)benzoate was prepared as follows: To a hot stirred mixture of 26.0 g. of ethyl 4-amino-2 (Z-diethylaminoethoxy)benzoate;24.1 g. of zinc dust, 22.6 g. of glacial acetic acid and 450 m1. of dry benzene was added 8.0 g. of n-butanal (n-butyraldehyde) dissolved in 50 ml. of dry bon zene over a fifteen minute period. After the mixture had been stirred for one hour, an additional 1 ml. of n-butanal was added and stirring continued for an additional fifteen'minutes. The zinc acetate was filtered ofi and washed with hot dilute acetic acid and benzene. The cooled filtrate was yl. b The crystalline base melted at l07.3l08.5 0. (con). Calod. for omnuNgoaz N 9.58.

Calcd. for CrIHzo QOa: bi 9.14.

Calcd. for G18H28Nl031 ND, 8.74.

Caled. for CwHazNgOfl ND, 9.52.

Caled. for GmH24N2O4 ND, -09. N 8.78.

D i The crystalline base melted at 94.295.6 0. (con). Calcd. for CnHzoNaOa: N 11. 11.

Found:

Found:

Found:

Found Found:

Found calcium sulfate, the benzene was removed by distilling invacuo, yielding, as a straw colored'oil, ethyl 4-n-butylamino-2- (2-diethylaminoethoxy) benzoate. This ester was converted into its monohydrochloride salt as follows: Eleven grams of the ester was dissolved in ethyl acetate and was treated with an excess of 20% by weight of ethanolic hydrogen chloride, whereupon a gummy material separated immediately. The supernatant liquid was decanted from the gum and the latter was triturated twice withwarm ethyl acetate. The gummy material was then dissolved in a minimum amount of hot ethanol, 12 g. of ethyl 4-nbutylamino 2 (Z-diethylaminoethoxy)benzoate was added and the solution was cooled. Absolute.

ether was then added to turbidity, whereupon a cream colored crystalline precipitate separated. The mixture was diluted to about 500 ml. with absolute ether. The precipitate was collected and recrystallized once from absolute ethanol-absolute ether'with decolorization, using decolorizing charcoal, and a second time, with decolorization, from ethanobethyl acetate. ethyl 4.n-butylarnino-2- (Z-diethylaminoethoxy) benzoate hydrochloride, M. P. 1'60.5161.8 0. (con).

AnaZr-Calcd. for C19Ha2N20a.HC1: N 7 .51; G1. 9.50. Found: N 7.36; 01.9.45. When the above procedure is followed but using n-propanal, n-pentanal and n-heXanal, in place of n-butanal, the resulting products, in the form of their monohydrochlorides, are ethyl 4-n-propylamino 2 (2 diethylaminoethoxy)benzoate, ethyl 4-n-amylamino-2- (2-diethy1an'linoethoxy)-,

benzoate and ethyl 4-n-hexylamino-2- (2.-diethyl-,,

using, in place of ethyl 4-amino-2-(2-diethylaminoethoxy) benzoate, methyl 4-am1no-2 [-3- (1- There was thus obtained piperldyl)propoxylbenzoate, n-propyl 4-amino'-:* pi'peridyl) ethoxy] -ben- 2-[2-'(2,6-dimethy1 1 zoate, n-butyl 4 amino-2-[2-(2-methyl-l-piperidyl)ethoxylbenzoate or ethyl 4-amino-2- [2-(4-morpholinyl) ethoxylbenzoate, there is obtained, in the form of their monohydrochlorides, methyl 4-n-buty1amino-2-[3 (l-piperidyDpropoxyl-benzoate, n-propyl 4-n-butylamino-2E2- (2,6-dimethyl-l-piperidyl)ethoxy] benzoate, nbutyl 4-n-butylamino-2 [2 (Z-methyl-l-piperidyDethoxylbenzoate or ethyl 4 n butylamino-2-[2 (4 morpholinyl)ethoxylbenzoate,

respectively.

Ethyl 4-(5-hydroxyamylamino) 2-(2-diethylaminoethoxy)benzoate was obtained, as an oil, following the above procedure but using 26.0 g. of ethyl 4-amino-2-diethylaminoethoxy) benzoate, 11.3 g. of 5-hydroxypentanal, 24.1 g; of zinc dust, 22.6 g. of glacial acetic acid and 500 ml. of dry benzene. Ethyl 4 (5-hydroxyamylamino) 2 (2 diethylaminoethoxy)-benzoate monohydrochloride, M. P. 132.2-l33.4 C. (cor.) was obtained following the procedure above for preparing ethyl 4 n-butylamino 2-(2-diethylaminoethoxy benzoate monohydrochloride.

Anal.Calcd. for C20H34N2O4.HC12 N 6.95; CI, 8.79. Found: N 7.07; Cl, 9.05.

When the above procedure was followed but using, in place of ethyl 4-amino-2-(2-diethylaminoethoxy)benzoate, n-propyl 4-amino-2-(2- diethylaminoethoxy)benzoate and ethyl 4-amino-2-[2 (2,6 dimethyl 1 piperidyD-ethoxylbenzoate, there was obtained, as oils, n-propyl 4-(5 hydroxyamyl-amino) 2 (Z-diethylaminoethoxy)benzoate and ethyl 4-(5-hydroxyamylamino)-2-[2 (2,6-dimethyl l-piperidyl) ethoxylbenzoate, respectively. 7

When the above procedure is followed but using'in place of 5-hydroxypentanal, 3-hydroxypropanol, 4-hydroxybutanal, 3-hydroxybutanal or B-hydroxyhexanal, there is obtained, in the form of their monohydrochlorides, ethyl 4-(3- hydroxypropylamino) 2 (2 diethylaminoethoxy)benzoate, ethyl 4-(4-hydroxybutylamino) -2- (Z-diethylaminoethoxy) benzoate, ethyl 4- 3 hydroxybutylamino) 2 (2 -diethy1aminoethoxy)benzoate or ethyl 4-(6-hydroxyhexylamino) -2- Z-diethylaminoethoxy) benzoate, respectively.

Ethyl 4-(3-hydroxy-2,2 dimethylpropylamino)-2,- [2 (2,6-dimethyl-l-piperidyl)ethoxylben zbate was prepared following the above procedures but using 19 g. of ethyl 4-amino-2-[2- (2,6-dimethyl l piperidyl) ethoxylbenzoate, 7.32 g. of 3-hydroxy2,2-dimethylpropanal, 15.5 g. of zinc dust, 14.5 g. of glacial acetic acid'and 500 m1. of. dry benzene. The resulting product, a pale yellow mobile oil, crystallized when triturated. The crystalline material was recrystallized twice from benzene, with decolorization using decolorizing charcoal, yielding ethyl 4-(3-hydroxy 2,2 dimethylpropylamino) 2-[2- (2,6- dimethyl-1 -piperidyl)ethoxylbenzoate, M. P. 90.0-9l.0 C. (con) [dried in vacuo at 65 C.].

AnaZ.-Calcd. for C23H33N204Z C, 67.94; H, 9.42; N 6.89. Found: C, 63.06; H, 9.31; N 6.81.

Alternatively, the foregoing reductive alkylations can be carried out using, in place of zinc dust and glacial acetic acid, hydrogen under.

pressure in the presence of a hydrogenation catalyst such as platinum.

Other lower alkyl 4-all ylaminoor 4-hydroxyalkylamino-Z (tertiaryaminoalkoxy)benzoates which can be prepared according to the above procedures using the appropriate alkanal or hying: ethyl 4-n-butylamino-2-(2-dimethylamin0- l-prop'oxy)benzoate; isobutyl 4-n-propylamino- 2-[3 (l-pyrrolidyl)propoxylbenzoate; ethyl 4- (3-hydroxypropylamino)-2-[2-(2,5- dimethyl '1 pyrrolidybethoxylbenzoate; methyl 4 nhexylamino-Z (4-dimethylaminobutoxy)benzoate; n-propyl 4-n-amylamino-2-[2-di-n-butylamino) ethoxyl -benzoate; n butyl 4 n butylamino-2 '[3-(4 methyl-l-piperidyl)propoxylbenzoate; n-hexyl 4 n-propylamino-2-[2-(3- ethyl-l-piperidyl) ethoxylbenzoate; n-amyl 4- (5 hydroxyamylamino) 2-[3 (Z-methyl-lpyrrolidyl) propoxy] benzoate; and the like.

Alternatively, the lower alkyl 4-alky1aminoand 4-hydroxyalkylamino 2 (tertiary-aminoalkoxy)benzoates of our invention can be prepared by direct alkylation of the corresponding 4-amino compounds. This mode of alkylation is illustrated by heating ethyl 4-amino-2-(2-diethylaminoethoxy) -benzoate with methyl iodide,

ethyl bromide, 2-hydroxyethyl bromide, n-propyl iodide, n-butyl bromide or 5-hydroxypentyl chloride in the presence of a hydrogen halide acceptor such as potassium carbonate to yield, re

spectively, ethyl 4-methy1amino-2-(2-diethylaminoethoxy)benzoate, ethyl 4-ethylamino-2- (2 diethylaminoethoxy)benzoate, ethyl 4-(2- hydroXyethylamino)-2 (2-diethylaminoethoxy) benzoate, ethyl 4-n-propylamino-2-(Z-diethylaminoethoxy)benzoate, ethyl 4-n-butylamino-2- (Z-diethylaminoethoxy)benzoate or ethyl 4-(5- hydroxyamylamino) -2 (2-diethylaminoethoxy) benzoate.

(4) Lower alkyl 4-m'tro-2-(terttary-aminoalkoasywenzoatev quaternary ammonium salts These compounds are prepared by treating the corresponding lower .alkyl 4-nitro-2-(tertiaryaminoalkoxy)benzoates with an alkyl or benzyl ester of an inorganic or organic acid of the type described hereinabove. The reaction is illustrated by the following examples.

Ethyl 4-nitro-2-(2 diethylaminoethoxy) benzoate methiodide was prepared as follows: To a solution of 6 g. of ethyl 4-nitro-2-(2-diethyl aminoethoxy)benzoate in 50 m1. of ethyl acetate Was added 15 ml. of methyl iodide. After about five minutes at room temperature, the mixture turned cloudy. It was then refluxed for one and one-half hours 'to ensure completion of the reaction. After about five minutes of refluxing, crystals formed and the color of the reaction mixture changed from deep orange to very pale yellow. The reaction mixture was cooled in ice, filtered and the product was washed with ethyl acetate. This material was recrystallized once from isopropanolethyl acetate and once from isopropanol alone, yielding, ethyl 4-nitro-2-(2- diethylaminoethoxy)benzoate methiodide, M. P.

17 2-(2-diethylaminoethoxy) benzoate etho para.- toluenesulfohate;

Ethyl 4-nitro-2-[ 3-(l piperidyhpropoxylbenzoate methiodide wasprepared as follows: Ten 7 rams of ethyl 4 nitro 2 [3'(1-piperidyl) propoxylbenzoate hydrochloride was dissolved in about 150 ml. of water "and the solution was treated with an excess of sodium'bicarbonate. The mixture was saturated with sodium chloride and the oil that separated was extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous calcium sulfate, concentrated to a volume of about 125 ml., cooled and treated with 15 ml. of methyl iodide, whereupon precipitation took place slowly. To ensure completion of the reaction, the mixture was refluxed for thirty minutes, cooled and filtered; and the product was washed with ethyl acetate. One recrystallization from absolute ethanol yielded ethyl 4-nitro-2-[3 (1 piperidyDpropoxylbenzoate methiodide, M. P. 166.9-1619" C'. (cor).

AnaZ.-Calcd. for CmHzvINzOs: I, 26.53; M0,, 2.93. Found: I, 26.30; M 2.99.

n-Butyl 4-nitro 2 (2- diethylaminoethoxy) benzoate methiodide was prepared following thev procedure described above for the preparation of ethyl 4-n-itro 2 [3-(1-piperidy1)propoxylbenzoate methiodide but using 10 g. of n-butyl 4- nitro-2- (Z-diethylaminoethoxy) benzoate hydrochloride, ml. of methyl iodide and 125 m1. of ethyl acetate. This methiodide melted at ll8.2-120.3 C. (cor.) when recrystallized from absolute ethanol-absolute ether.

AnaZ.Calcd. for C1aH29IN2O5: I, 26.42; M0,. 0

0 TABLE .III

, by distillingqin vacuo.

"treated with'ethyl acetate and the solvent again ing charcoal, once from 'isopropanolre'thyl ace;-

dimethyl-l-pyrrolidyl) ethoxyl'benzoate methiodide; methyl 4-nitro-2 (4 dimet 1'iyl-aminc 'butoxy)benz'oate methiodide; n-propy'l 4 nitro-z- [2- (di-n butylamino) ethcxylbenzoate -'-m eth-iodide;

dide; and the like.

(5) Lower alkyl V4- amino-2-(tertiary-amiwoalkoxwbenzoate quaternary ammonium salts Ethyl l n itro-zz-lZ-diethylaminoethoxy) benzoate methiodide (18.5 g.) was mixed with 400 mg. of platinum oxide monohydrate and enough absolute ethanolto bring the total volume to 150 ml., and was treated with hydrogen under pressure at room temperature. The reaction took about fifteen minutes. The catalyst was filtered off and washed with absolute ethanol. The combined filtrate and washings were taken to dryness in vacuo and the residue was treated with ethyl acetate and the ethyl acetate was removed The residue was again removed invacuo, therebyw yielding .a crystalline residue. Thisw'as fl'ltered' and 'washed well with? I33: i)1 1TTR Rx I DOOR:

Analysis, Percent 71 .NRR1 B2 Formula Nun, I I

i Calcd. Found Qalcd. l oum'l 2 (CH-3)2 .CQHs 1902-1012 C'nHgilNz'Ot 6. 0 6.38. "29.92 30.110 2 N(O7,Ha)z .l'1-C3H7 1443. 244456 C17H27IN505 3. 00 3. 04 27. 22 .27..00 2H5)2 02H. Mao-149:6 CnHzv'INzOa 3.00 3.10 27. 22 27.30 2 NC5H C2115 hull-148.?) G17H25IN2O5 3. 02 3.03 2'1. 34: 20.90 J 2 NG H CzHs 159. 8-1610 OlBHW NZOfi 2- 93 2. 2 2 -53 .26-20. 2 NCTHU- C2E 192. 3492. 9 CwHztINaOs '2. 2.82 25.78 25. 40 3 NCtHn v C2155 165. 5-1605 CmHnINm I 2.85 2.87 25. 78 2.5.40 2 N C4H30 GJH5 5-191. 3 CmHzgINzua .3. 00 3. 02 .27. 22 26. 9.0 '3 NCl'HsO @2115 161. 1-101. 7 C17H25IN2O5 'j 2. 92 '2. 91 i 26:42 26. 3O 2' N(CzH5) CH? 162.5:163J0 GmHgs'INzOs 3. 19 3.22 28.96 28.80 2 NClHtO .CH3 209.'0.2l1..0 CmHnINzOs 3.09 3.17 28.06 E 27.88

tateand once fromacetone. The resulting product, ethyl 4 amino 2 (2-diethylaminoethoxy) benzoate methiodide, melted at 1392-1411? (3.

Andl..Calcd; or Gal-121N203: c. 45:50,-

6.45; I, 30.05.- Found; C, 45.28; H, .6158; .1, "29.70.

- When the above procedure is followed but us -,1

n-butyl 4-nitro-2- [3--('4-methyl-1-piper{ idyllpropoxylbenzoate methiodide; n-hexyl 4- nitro 2- [2 (B-ethyI-I-piperidyl) ethoxylben-' zoate methiodide; -n' amyl 4 nitro 2- [3 '('2 methyl- 1 pyrrolidyl) propoxylbenzoate methio-' ing, in place of ethyl 4-nitro-2-(Z-diethylaminoethoxy)benzoate methiodide, ethyl 4 -ni tro-2-- (Z-diethylaminoethoxy)benzoate methobromide, ethyl 4-nitro-2- (2-diethylaminoethoxy) benzoate ethochloride, ethyl 4-nitro-2(Z-diethylaminm ethoxy) benzoate n-propiodide, ethyl 4enitro-2-x Y2-diethylaminoethoxy) benzoate benzochloride or ethyl 4-nitro-2- (Z-diethylaminoethoxy) benzoate isopropanol.

AnaZ.Calcd. for 01. 13.111.63. 1. 23.18;"ND,l

$.22. Found: I, 28.00; ND, 6.33. 1

Additional lower alkyl 4-amin0-2- (tertiaryaminoalkoxy benzoate methiodides prepared ac-. cording to the above procedure are given in Table,

etho-para-toluenesulfonate, there is obtained, re- IV.

' TABLE IV lTTH:

0 (GHmlTIR R,

o 0 o R:

Analysis 7 f i o n NRR1 R: f Formula 7 I N1? Calcd. Found Calcd. Found 2 M02115). 20.15. 127. 4-129. 6 CnHmINzOs 29. 09 2s. 91 1 e. 42 e. 52 a meme. 01115 125. 0426. 0 C11H21IN2O9 29. 09 29. 93 s. 42 6.35 2 NCsHm 02H; 167. 1468. 4 C17H27IN203 29. 22 29. 41 e. 45 s. so 2 N-C1H14 CzH 123. 4-125. 4 CmH31INzO3 27. 45 27. 59 6. 06 5. 84 2 NCAHsO" 02115 182. 7-183. 7 CH2$IN204 29. 09 29. 12 6. 42 6. .40 3 Noimo 0.115 151. 9-153. 1 O17HZ7IN204 2s. 18 28.13 6.25 6.25 2 N(CH9)1 02115 202. 2202. 9 O14H2aIN2Oa 32.19 32. 41 7.11 7.11 2 N(C 2H52 2. CH3 127. 4-129. 0 CH25IN203 31. 09 29. 97 6. 86 7. 00

a NCsHm=l-plperidyl spectively, ethyl 4-amino-2- (2-diethylaminoethoxy)benzoate methobromide, ethyl 4-amino-2- (2 diethylaminoethoxy)benzoate ethochloride,-.

piperidyl)propoxylbenzoate methiodide 200 mg.

of platinum oxide monohydrate and 150 ml. of absolute ethanol was heated to and was treated with hydrogen under pressurefor one hour. The catalyst was filtered ofi and the filtrate was taken to dryness under reduced pressure. Ethyl acetate was added to the remaining material and the resulting solution was taken to dryness under reduced pressure. The material that remained crystallized when triturated with isopropanol. Three recrystallizationsrof this material from absolute ethanol yielded, ethyl 4- amino-2- [3- (l-piperidyl) propoxy] benzoate methiodide, M. P. 150.1-150.6 C. (con).

AnaL-Calcd. for C18H29IN203: I, 28.31; ND, 6.25. Found: I, 28.61; ND, 6.09. When the foregoing procedure is followed but using ethyl 4-nitro-2- [3- (Z-methyl-l-piperidyl) propoxylbenzoate methiodide in place of ethyl 4-nitro-2- [3- (l-piperidyl) propoxylbenzoate methiodide, there is obtained ethyl 4-amino2-[3- 2-methyl l-piperidyl) propoxyl benzoate methiodide. p n -Butyl .4 amino-2- (2-diethylaminoethoxy) benzoate'm'ethiodide was prepared according to the procedure described in the preceding example but using 5.0 g. of n-butyl 4-nitro-2-(2-diethyl-- aminoethoxy)benzoate methiodide,v 200 mg. of platinum oxide monohydrate and 150 m1. of ab- Additional lower alkyl 4- am ino-2-(terti'a ry aminoalkoxy benzoate methiodides which can-be prepared according to the foregoing procedure include the following: ethyl 4-.amino-2-(2-dimethylamino 1 propoxy) benzo-ate methiodide;

isobutyl 4-amino-2-[3 (l pyrrolidy1)propoxy]- benzoate methiodide; ethyl 4-amino-2-[2-(2,5- dimethyl 1 pyrrolidyl)ethoxylbenzoate methiodide; methyl 4-amino-2-(4-dimethylaminobutoxy benzoate methiodide; n-propyl 4-amino-2- [2- (di-n-butylamino) ethoxylmethiodide; n-butyl 4-amino 2 [3 4 -methyl-1-piperidyl)propoxylbenzoate methiodide; n-hexyl 4-amino-2- [2- (3-ethyl-1-piperidyl) ethoxy] benzoate methiodide; n-amyl 4-amino-2-[3- (z-methyl-l-pyrrolidyDpropoxylbenzoate methiodide; and the like.

I (6) Lower alkyl 4-allcylamz'no and 4-hydroxi1- aZkyZamino-Z- (tertiary-aminoalkoxy) benzoate quarterna'ry ammonium salts These compounds where the 4-alkylor 4-hydroxyalkyl radical, designated hereinabove as R3,

have from three to six carbon atoms are prepared preferably by reductively alkylating the corresponding lower alkyl 4-amino-2-(tertiary-aminoalkoxy)benzoate quaternary. ammonium salts with hydrogen under pressure and an alkanal or a hydroxyalkanal having three to six carbon atoms, in the presence of a hydrogenation catalyst. This preparation and the products obtained thereby are illustrated by the following examples.

Ethyl Y 4 n butylamino-2- (diethylaminoethoxy benzoate methiodide can be prepared as follows: A mixture of 10 g. of ethyl 4-amino-2-(diethylaminoethoxy)benzoate methiodide, 5 gof ethyl 4 amino-2- (2 -diethylam=inoeth'oxy ben 'zm ate methobrom'ide, ethochloride, n propi'odide, benzochloride or etho para toluenesulfonate, there is obtained, respectively, ethyl 4-n-:butylamino- 2- (2-diethylaminoethoxyberizoatemethobromide, ethyl 4 n -butylamind Z- (2 diethylaminoethoxy benzoate ;ethoch1oride, ethyl 4m butylamino .2 -(2-diethylaminoethoxy)'benzoate n-propiodide, ethyl 4-n-butylamino-2-l2 diethylaminoethoxymenzoate 'benzochlorid'e or ethyl 4- n-buty1amino-2-(2-diethylaminoethoxyDbenzo ate etho-para-toluenesulfonate.

When the above procedure is followed but using, in place of ethyl 4-amino-2-(2-diethylaminoethoxy benzoate methiodide, ethyl 4- amino 2 [3 (1 piperidyl)propoxylbenzoate methiodide, ethyl 4-amino-2-['3-(2-methyl lpiperidyl)propoxylbenzoate methiodide, n-butyl 4 amino 2 (2 diethylaminoethoxy)benzoate methiodide, ethyl 4-ami-no-2-[2(2,6 dimethyll-piperidyl )ethoxylbenzoate methiodide, ethyl 4 amino 2 [3 (4- morpholinyllpropoxylbenzoat'e 'methiodide, ethyl 4-am'ino-.2-(2-dimethylaminoet'hoxy')benzoate methiodide or methyl 4-amino-2- (Z-diethylaminoethoxy) benzoate methiodide andusing the appropriate respective alkanal or hydroxyalkanal, therefis obtained, respectively, ethyl 4'-n-pro.py'lamino -2- [3 (l piperidyl)propoxylbenzoatemethiodide, ethyl 4-n-amy1amino2- [3- (2'-methyl-1-p'iper.-

idyl) propoxyl benzoate methioc lide, jnebu'tyl 4-'n-' hexylamin'o 2 2 diet'hylaniiiwethoxy) benzoate methiodide, ethyl 4-(5ehydroxyamylaminol- 2 [2 (2,6 dim'ethy'l 1 piperidy'l) ethoxyllbenzoate methiodide, ethyl 4--(3-hydroxybutylamino) 2 [3 (4 morpho1inyl)propoxy]benzoate methiodide, ethyl 4-n-butylamino-2-(2- dimethylaminoethoxy)benzoate methiodide or methyl 4- (4-hydroxybutylamino) -2- (2-diethylaminoethoxy) benzoate methiodide.

Alternatively, the lower alkyl 4-a1kylaminoand 4-hydroxyalkylamino- 2 (tertiary-'ainino-alkoxyibenzoate quaternary ammonium salts can be prepared by treating the corresponding lower alkyl 4-alkyl'aminoor 4-hydroXya1-ly1amino-2- (ter-tiary-amino'alkoxy) benzoatewith an alkyl or benzyl ester of an inorganic or; organic acidof the type described hereinabov'el "This rrio'de' of preparation is illustrated by treating isobut'yl "4- m'ethylamino-Z-(2-diethylaminoethoxy) benzeate, n-propyl 4-e'thylamino- 2-'(-2-diethylarninoethoxywenzoate or ethyl '4-(2-hydroxyethyb amino) -2- (2-diethylaminoethoxy benzoate 1 with methyl iodide to yield, respectively, isobutyl 4- methylamino 2 (2 diethylaminoethoxy.)benzoate methiodide, n-propyl 4'ethylamino-*2( 2=-diethylaminoethoxy)benzo'ate methiodid'e or ethyl 4-(2-hydroxyethylamino) 2 (2 diethylaminoethoxy) benzoate methiodide.

Additional lower alkyl 4-alky'laminoand 4- hydroxyalkylamino 2 (tertiary aminoalkoxy) benzoate methiodi'des which can be prepared according to the foregoing procedure include the following: ethyl 4-n-butylamino-2-(Z-dimeth- 2221 ylaminod-propoxybbenzoate methiodide;. 'i'so butyl 4 n butylamino-z- [3F '(1-.pyrrolidylIpro'- poxylbenzoate methiodide; ethyl 4-(6-hydroxyhexylamino) 2 [2 (2,5 dimethyl l pyrrolidyDethoxylbenz-oate methiodide; methyl 4- (3 hydroxy 1 butylamino) 2 (4 dimethylaminobutoxy benzoate methiodide; n-propyl 4- (3 hydroxypropylamino) 2 [2 (di nbutylamino)ethoxylbenzoate methiodide; nbutyl 4-n-pr-opylamino 2- [3- (4-methyl-l-piperidyllpropoxylbenzoate methiodide; n-hexyl J4- is'o'butyiamino '21-'[2 (3 ethyl 1 -jpiperidy1) ethoxylbenzoatefmethiodide; n-amyl 4-n-hexy1 amino 2 [3 (2: methyl 1 pyrrolidyllpropoxylbenzoate methiodide; and'th'e like.

We claim; 1. A quaternary ammonium salt having; the formula where Z is 'am'ember of the group consisting of nitro, amino, amino, X is a lower alkylene r'ad'icalwhose two free valence bonds are on different carbon atoms,

NRR1 is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated)-1-piperidyl, l-pyrrolidyl, (loweralkylated) -1-pyrrolidy1 and morpho'linyl, R2 is a lower COOR:

where X is a lower ialkylene'radical whose two free valence bonds are on different carbon atoms, R2 is a lower alkyl radicahRl is a lower alkyl radical and An is a non-toxic anion of a strong acid.

3. Arquaternary ammonium salt cilia lower alkyl 4-amino-2--(:diethylaminoalkoxyl)benzoate havingthe formula where X is a lower alkylen'e radical whose two free valence bonds are von different carbon atoms,

R2 is a lower alkyl radical, R4 is a lower alkyl radical ,andAnis a non-toxic anion of a strong alkylamino and hydroXyalkyL' 2a alkyl 4-amino-2- (tertiary aminoalkoxy) benzoate having the formula where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms; R2 is a lower alkyl radical, NRR1 is a l-piperidyl radical, R4 is a lower alkyl radical and An is a non-toxic anion of a Strong acid. r 4 r 5. A quaternary ammonium salt of an ethyl 4- amino-2- (dialkylaminoalkoxy) benzoate having the formula where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms,

R4 is alower alkyl radical and An is a non-toxic anion of a strong acid.

6. A quaternary ammonium salt of an ethyl fl amino-2- (diethylaminoalkoxy) benzoate having the formula NH: v

where Xis a lower alkylene radical'whose two free valence bonds are on different carbon atoms, NRRi is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated) -1- piperidyl, l-pyrrolidyl, (lower alkylated)-1-pyr roldyl and morpholinyl, R2 is a lower alkyl radical, R4 is a member of the group consisting of a lower alkyl radical and a benzyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding lower a1- kyl 4 nitro 2 (tertiary-aminoalkoxy) benzoate with an ester having the formula R4-An and treating the resulting lower alkyl 4-nitro-2-(tertiaryaminalkoxy)benzoate quaternary ammonium salt with a reducing agent efiective to; reduce nitro groups to amino groups.

9. A process of preparing a quaternary am- NHi where X is a lower alkylene radical whose two free valence bonds are on diiferent carbon atoms, R2 is a lower alkyl radical, R4 is a lower alkyl radical and An is a non-toxic anion Ofa strong acid, which comprises treating the correspondr ing lower alkyl 4-nitro-2-(dialkylaminoalkoxy) benzoate with an ester having the formula Ri-An and treating the resulting lower alkyl e-nitro-2-' (dialkylaminoalkoxy)benzoate quaternary ammonium salt of a lower alkyl 4-amino-2-(dial I kylaminoalkoxy) benzcate having the formula monium salt with a reducing agent effective to reduce nitro groups to amino groups.

10. A process of preparing a quaternary ammonium salt of a lower alkyl 4-amino-2-(diethylaminoalkoxy benzoate having the formula where Xis' a lower alkylene radical whose two free valence bonds are on different carbon atoms, R2 is a lower alkyl radical, R4 is a lower alkyl radical and An is a non-toxic anion of a strong acid, which comprises treating the correspond-,

ing lower alkyl 4-nitro-2-(diethylaminoalkoxy)- benzoate with an ester having the formula R4-An and treating the resulting lower alkyl 4-nitro-2- (diethylaminoalkoxy)benzoate quaternary ammonium salt with a reducing agent effective to reduce nitro groups to amino groups.

11. A process of preparing a quaternary ammonium salt of a lower alkyl 4-amino-2-(tertiary-aminoalkoxy)benzoate having the formula 12; A process of preparing-a quaternary ammonium salt of ethyl 4-amino-2-(dialkylaminoalkoxy benzoate having the formula NHz I I CO 0 02115 where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms, R4 is a lower 'alkyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding ethyl 4 nitro 2 (dialkylaminoalkoxy)benzoate with an ester having the formula Ri-An and treating the resulting ethyl 4-nitro-2- dialkylaminoalkoxy) benzoate quaternary ammonium salt with a reducing agent effective to reduce nitro groups to amino groups.

13. A process of preparing a quaternary ammonium salt of ethyl' i-nitro-z-(cliethylaminoalkoxy)benzoate having the formula o o 02m where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms, R4 is a lower alkyl radical and A11 is a non-toxic anion of a strong acid, which comprises treating the corresponding ethyl 4 nitro 2 (diethylaminoalkoxy)benzoate With an ester having the formula Rl-An and treating the resulting ethyl 4-nitro-2- (diethylaminoalkoxy) benzoate quaternary ammonium salt with a reducing agent effective to reduce nitro groups to amino groups.

14. A process of preparing ethyl 4-nitro-2-(2- diethylaminoethoxy)benzoate methiodide, which comprises treating ethyl 4-nitro-2-(2-diethylaminoalkoxyybenzoate with an ester having the treating the resulting ethyl 4-nitro-2-(2-diethylaminoethoxy) benzoate methiodide with a reducing agent effective to reduce nitro groups to amino groups.

15. Ethyl 4-amino-2- [Z-(I-piperidyl) ethoxy] benzoate methiodide.

RAYMOND O. CLINTON. STANLEY C. LASKOWSKI.

References Cited in the file of this patent Moore: J. of American Pharmaceutical Association, July 1944, vol. 33, pages 193 204. 

1. A QUATERNARY AMMONIUM SALT HAVING THE FORMULA 